Abstact

Human serum albumin (HSA) is a ubiquitous, multifunctional protein responsible for the systemic distribution of both endogenous metabolites and exogenous pharmaceuticals. Its inherent properties, particularly its ability to seep into tissues and its multiple ligand-binding sites, have rendered HSA an attractive vehicle for nanoparticle-based drug delivery systems, particularly for cancer targeting. In this study, we present high-resolution crystallographic data revealing two distinct dimerization patterns of HSA (Protein Data Bank [PDB] ID: 9V61) obtained under high-concentration crystallization conditions, along with results from dipyridamole docking. Both dimer types demonstrate extensive interface areas and a significant number of electrostatic interactions. Comparative analysis with a previously reported dimer structure (PDB ID: 3JQZ) and other high-interface-area structures (PDB ID: 5Z0B, PDB ID: 8CKS) indicates similarities in contact regions but unique residue-level differences in bonding interactions. Interface surface area distribution and space group histograms further support the rarity and potential physiological relevance of the identified dimer forms. Importantly, these dimer configurations do not disrupt Sudlow's drug-binding sites, as the dipyridamole docking analysis shows strong affinity for sites I and III without affecting their utility in engineered drug delivery. Our findings open new avenues for structure-based mutagenesis and nanoparticle design strategies centered on HSA dimerization dynamics.